ABSTRACT The Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins is dedicated to cancer research, education and training, and care, with an overarching goal of expeditiously and strategically applying new knowledge to improve prevention, screening, detection, diagnosis and treatment of cancer in Maryland and throughout nation and the world. Through targeted outreach and research, cancer outcomes disparities are decreasing in SKCCC's catchment area, but they remain a challenge and a focus at SKCCC. This application requests continued Cancer Center Support Grant (CCSG) funding for SKCCC's Research Programs and Cores. The SKCCC comprises a multidisciplinary, interdepartmental center of The Johns Hopkins University (JHU), encompassing 34 departments in five schools. The scientific Programs of the SKCCC organize and orient the broad base of cancer research throughout JHU into teams focused on rapid translation to the clinic and to populations inside and outside its catchment area. Research conducted at SKCCC includes discovery research into the molecular genetics of human tumorigenesis, clinical trials of new cancer treatments and epidemiologic analyses of lifestyle influences on cancer mortality. The SKCCC is a leading cancer center that is providing insights into the fundamental nature of different cancers and elucidating the thousands of somatic genetic and epigenetic alterations that mark the differences from case to case. This body of work has fueled an emerging understanding that the ultimate control of cancer will require individualizing cancer care using approaches that can be deployed at a population scale. To accomplish this mission, SKCCC took critical input from its External Advisory Board and has strategically evolved since the last CCSG to: 1) augment the clinical and population impact of the discovery pipeline in cancer genetics, epigenetics and immunology generated by discipline-oriented Programs; 2) maximize the translational research output of disease-specific Programs, emphasizing the exploration of new concepts in scientifically driven clinical trials; and 3) position the population-oriented Program to identify, understand and overcome barriers responsible for disparities in cancer outcome in the catchment area. The nine SKCCC Research Programs include four discipline-oriented Programs: Cancer Biology (CB; Baylin, Velculescu), Cancer Immunology (CI; Pardoll, Drake), Cancer Molecular and Functional Imaging (CMFI; Bhujwalla, Pomper), and Cancer Chemical and Structural Biology (CCSB; Berger, Liu); four disease- specific Programs: Hematologic Malignancies and Bone Marrow Transplantation (HMBMT; Ambinder, Jones, Levis), Prostate Cancer (PC; Pienta, Denmeade, Lupold), Breast and Ovarian Cancer (BOC; Stearns, Shih), and Brain Cancer (BC; Grossman, Brem, Laterra); and one population-oriented Program: Cancer Prevention and Control (CPC; Platz, Roden). These Programs are supported by fifteen Cores, one developing Core (described in Developmental Funds) and a dedicated leadership team.